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Gene expression profiling of the peripheral blood mononuclear cells of offspring of one type 2 diabetic parent

  • Sher Zaman SafiEmail author
  • Rajes Qvist
  • Karuthan Chinna
  • Muhammad Aqeel Ashraf
  • Darishiani Paramasivam
  • Ikram Shah Ismail
Original Article

Abstract

Several lines of evidence from studies of both twins and offspring of people with type 2 diabetes have shown the importance of genetics in its pathogenesis. Impaired glucose tolerance (IGT) may reflect these genetic changes during the prediabetic stage. Thus, we performed a comprehensive analysis of the gene expression profiles of the peripheral blood mononuclear cells among offspring of one type 2 diabetic parent with normal glucose tolerance and impaired glucose tolerance in comparison to newly diagnosed diabetics and normal controls. Data were analysed from offspring of one type 2 diabetic parent. Gene expression profiles of 84 genes related to insulin-responsive genes were analysed using human insulin signalling pathway array. Of the 84 genes, 42 diabetic genes had at least a twofold change in expression for at least one comparison between the diabetic subjects, offspring with NGT and offspring with IGT as compared with controls. The most significant findings were that FOXP3 and SNAP25 were highly expressed in the offspring with IGT as compared with the controls, with a sixfold change in expression. The differential expression of the 42 genes among the offspring with IGT mainly demonstrates a defect in insulin secretion which suggests β cell dysfunction. The preponderance of experimental evidence favours the presence of impaired rather than excessive insulin secretion in the offspring before the development of IGT and thus supports the concept that the initial lesion in type 2 diabetes may involve impaired insulin secretion rather than insulin resistance. The results from our study suggest that β cell dysfunction starts early in the pathologic process and does not necessarily follow the stage of insulin resistance.

Keywords

Type 2 diabetics Impaired glucose tolerance Normal glucose tolerance PBMCs FOXP3 SNAP25 

Notes

Acknowledgments

The work of Karuthan Chinna was supported by University of Malaysia/Ministry of Higher Education (UM/MOHE) High Impact Research Grant E000010-20001. Language editing was provided by Barbara Every, ELS, of BioMedical Editor.

Supplementary material

13410_2015_369_MOESM1_ESM.docx (25 kb)
Table S1 List of 84 diabetic genes with controls used in our study (DOCX 24 kb)
13410_2015_369_MOESM2_ESM.docx (16 kb)
Table S2 Genes with at least a twofold change for at least one comparison between the T2D subjects and the offspring with NGT and IGT as compared with controls (DOCX 15 kb)

References

  1. 1.
    BennettPH BC, TuommilehtoJ ZP. Epidemiology and natural history of NIDDM: non obese and obese. In: Alberti KGMM, De Fronzo RA, Keen H, Zimmet P, editors. International textbook of diabetes mellitus. Chichester: Wiley; 1992. p. 148–69.Google Scholar
  2. 2.
    Ebelin SC. Genetics of type 2 diabetes: an overview for the millennium. Diabetes Technol Ther. 2000;2:391–400.CrossRefGoogle Scholar
  3. 3.
    McCarthy MI, Hitman GA, Shields DC, Morton NE, Snehalatha C, et al. Family studies of non-insulin dependent diabetes mellitus in South Indians. Diabetologia. 1994;37:1221–30.CrossRefPubMedGoogle Scholar
  4. 4.
    HaffnerSM SMP, Hazula HP, Pugh H, Patterson JK. Increased insulin concentrations in non-diabetic offspring of diabetic patients. Nengl J Med. 1988;319:1297–301.CrossRefGoogle Scholar
  5. 5.
    Lillioja S, Mott DM, Howard BV, Bennett PH, Yki-Järvinen H, et al. Impaired glucose tolerance as a disorder of insulin action: longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 1988;318:1217–25.CrossRefPubMedGoogle Scholar
  6. 6.
    Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int. 2014;2014. doi: 10.1155/2014/801269.
  7. 7.
    Poulsen P, Kyvik KO, Vaag A, Beck-Nielson H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose signalling population based twin study. Diabetologia. 1999;42:139–45.CrossRefPubMedGoogle Scholar
  8. 8.
    Safi SZ, Qvist R, Yan GO, Ismail IS. Differential expression and role of hyperglycemia induced oxidative stress in epigenetic regulation of β1, β2 and β3-adrenergic receptors in retinal endothelial cells. BMC Med Genomics. 2014;7:29. doi: 10.1186/1755-8794-7-29.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Stegenga ME, Van de Crabben SN, Dessing MC, Pater JM, Van den Panggart PS, et al. Effect of acute hyperglycaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans. Diabet Med. 2008;25:157–64.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Choong CL, Jun M, Hong CT, et al. The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Med. 2006;147:126–32.CrossRefGoogle Scholar
  11. 11.
    Gokulakrishnan K, Mohanavalli KT, Monickaraj F, et al. Subclinical inflammation/oxidation as revealed by altered gene expression profiles in subjects with impaired glucose tolerance and type 2 diabetes patients. Mol Cell Biochem. 2009;324:173–81.CrossRefPubMedGoogle Scholar
  12. 12.
    Palsgaard J, Bronse C, Fredrichsen M, Dominguez H, Jensen M, et al. Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: differential regulation of insulin signalling pathways. PLoS One. 2009;4(e):6575.CrossRefGoogle Scholar
  13. 13.
    National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose tolerance. Diabetes. 1979;28:1039–47.CrossRefGoogle Scholar
  14. 14.
    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without the use of preparatory centrifuge. Clin Chem. 1972;18:499–503.PubMedGoogle Scholar
  15. 15.
    Zraika S, Dunlop ME, Proietto J, Andrikopoulos S. Elevated SNAP-25 is associated with fatty acid induced impairment of mouse islet function. Biochem Biophys Res Commun. 2004;317:472–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Eliasson L, GaisanoS VJ. Reduced stimulation by cAMP in insulin secreting calls over expressing truncated SNAP 25. Diabetologia. 2005;48:A172.CrossRefGoogle Scholar
  17. 17.
    Liston A, Katherine N, Andrew F, Jennifer L, Jeffery R, et al. Differentiation of regulatory Foxp3 + T cells in the thymic cortex. Proc Natl Acad Sci USA. 2008;105:11903–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wan JC. TGF-β regulates reciprocal differentiation of CD4 + CD25 + Foxp3 + regulatory T cells and IL-17-producing Th17 cells from naïve CD4 + CD25—T cells. In: Jiang and Shuiping (eds.) Regulatory T cells and clinical application. Springer: 2009. pp. 111–134.doi: 10.1007/978-0-387-77909-6- 7.Google Scholar
  19. 19.
    Harald VB, Jens N. What turns on Foxp3? Nat Immunol. 2008;9:121–2.CrossRefGoogle Scholar
  20. 20.
    Huehn J, Polansky JK, Hamann A. Epigenetic control of Foxp3 expression: the key to a stable regulatory T-cell lineage. Nat Rev Immunol. 2009;9(2):83–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Polansky JK, Kretchmer K, Freyer J, Floess S, Garbe A, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008;38:1654–63.CrossRefPubMedGoogle Scholar
  22. 22.
    Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Immunology. 2009;106:4793–8.Google Scholar
  23. 23.
    Jagannathan-BM MDME, ShinH RQ, Hasturk H, et al. Elevated proinflammatory cytokine production by a22ignal cell compartment requires monocytes and promotes inflammation in type 2 diabetes. Jimmunol. 2011;185:1162–72.CrossRefGoogle Scholar
  24. 24.
    Zuniga LA, Shen WJ, Joyce- Shaikh B, Pyatnova EA, Richards AG, et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol. 2010;185:6947–59.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sharma AM, Staels B. Peroxisome proliferator-activated receptor gamma and adipose tissue: understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metabol. 2007;92:386–95.CrossRefGoogle Scholar
  26. 26.
    Puigserver P, Spiegelmen BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78–90.CrossRefPubMedGoogle Scholar
  27. 27.
    Vimaleswaran KS, Radah V, Anjana M, Deepa R, Gosh S, Majumdar PP, et al. Effect of polymorphism in PPARGC1A gene on body fat in Asian Indians. International J Obes. 2006;31:563. doi: 10.1038/sj.ijo.0803228.CrossRefGoogle Scholar
  28. 28.
    Parton LE, Diraison F, Neill SE, Ghosh SK, Rubino MA, et al. Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile ignalli with oligonucleotide microarrays. Am J Physiol Endocrinol Metab. 2004;287:E390–404.CrossRefPubMedGoogle Scholar
  29. 29.
    Jeffrey E, Pessin, Alan RS. Signaling pathways in insulin action: molecular targets of insulin resistance. J ClinInves. 2000;106(2):165–9.Google Scholar
  30. 30.
    Lorella M, Jeffrey T, Sonika D, Dennis CS, Arun S, et al. Gene expression profiles of beta-cell encroached tissue obtained by laser capture microdissection from subjects with type 2 diabetes. Plos One. 2010;5(7):e11499.CrossRefGoogle Scholar
  31. 31.
    Herman C, Goke R, Richter G, et al. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion. 1995;56(2):117–26.CrossRefGoogle Scholar
  32. 32.
    Kamuichi K, Hasegawa G, Obayashi H, Kitamura A, Ishii M, et al. Leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) polymorphism is associated with diabetic nephropathy in type 2 diabetes mellitus. J Diabetes Complications. 2002;16:333–7.CrossRefGoogle Scholar
  33. 33.
    Jiyoung P, Sung SC, Hyun AC, Kang HK, Myeong JY, et al. Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals. Diabetes. 2006;55:2939–49.CrossRefGoogle Scholar
  34. 34.
    Xu J, Han J, Long YS, Lock J, Weir GC, et al. Malic enzyme is present in mouse islets and modulates insulin secretion. Diabetalogia. 2008;51(12):2281–9.CrossRefGoogle Scholar
  35. 35.
    Boni-Schnetzler M, Thorne J, Parmaud G, Marselli L, Ehes JA, et al. Increased interleukin-1 βmessenger ribonucleic acid expression in β cells of individuals with type 2 diabetes and regulation of IL-β in human islets by glucose and autostimulation. J Clin Endocrinol Metab. 2008;93:4065–74.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lupi R, Del Prato S. Beta cell apoptosis in type 2 diabetes: quantitative and functional consequences. Diabetes Metab. 2008;34 Suppl 2:56–64.CrossRefGoogle Scholar
  37. 37.
    Cerasi E, Kaiser N, Leibowitz G. Type 2 diabetes and beta cell apoptosis. Diabetes Metab. 2000;26(Suppl3):13–26.PubMedGoogle Scholar
  38. 38.
    Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta. 2002;1576:1–14.CrossRefPubMedGoogle Scholar
  39. 39.
    Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413:179–83.CrossRefPubMedGoogle Scholar
  40. 40.
    Trumper A, TrumperK HD. Mechanism of mitogenic and anti-apoptotic signalling by glucose-dependent insulinotropic polypeptide in β (INS-1)-cells. J Endocrinol. 2002;174:233–46.CrossRefPubMedGoogle Scholar
  41. 41.
    De Meyts P. The diabetogenes concept of NIDDM. Adv Exp Med Biol. 1993;334:89–100.CrossRefPubMedGoogle Scholar
  42. 42.
    Fida B, So JL, Neslihan G, Silva AA. From prediabetes to type 2 diabetes in obese youth. Diabetes Care. 2010;33(10):2225–31.CrossRefGoogle Scholar
  43. 43.
    Timon WVH, Walkyria P, Asimina M, et al. Disturbances in β-cell function in impaired fasting glycemia. Diabetes. 2002;51 Suppl 1:S265–70.Google Scholar

Copyright information

© Research Society for Study of Diabetes in India 2015

Authors and Affiliations

  • Sher Zaman Safi
    • 1
    Email author
  • Rajes Qvist
    • 1
  • Karuthan Chinna
    • 2
  • Muhammad Aqeel Ashraf
    • 1
    • 2
    • 3
  • Darishiani Paramasivam
    • 2
  • Ikram Shah Ismail
    • 1
  1. 1.Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  2. 2.Department of Social and Preventive Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  3. 3.Department of Geology, Faculty of ScienceUniversity of MalayaKuala LumpurMalaysia

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